17-39927109-G-T

Position:

• chr17-39927109-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_139280.4(ORMDL3):​c.-23+375C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000445 in 696,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: ORMDL3 NM_139280.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22

Genes affected

ORMDL3 (HGNC:16038): (ORMDL sphingolipid biosynthesis regulator 3) Involved in ceramide metabolic process. Acts upstream of or within several processes, including negative regulation of B cell apoptotic process; negative regulation of ceramide biosynthetic process; and positive regulation of protein localization to nucleus. Located in endoplasmic reticulum. Part of SPOTS complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS2: High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ORMDL3	NM_139280.4	c.-23+375C>A		intron_variant		ENST00000304046.7	NP_644809.1
ORMDL3	NM_001320802.2	c.-18+375C>A		intron_variant			NP_001307731.1
ORMDL3	XM_047437093.1	c.-18+320C>A		intron_variant			XP_047293049.1
ORMDL3	XM_047437094.1	c.-23+320C>A		intron_variant			XP_047293050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ORMDL3	ENST00000304046.7	c.-23+375C>A		intron_variant		1	NM_139280.4	ENSP00000304858.2
ORMDL3	ENST00000579695.5	c.-18+375C>A		intron_variant		1		ENSP00000464693.1
ORMDL3	ENST00000584000.1	c.-65C>A		5_prime_UTR_variant	1/4	4		ENSP00000464298.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000551 AC: 30 AN: 544498 Hom.: 0 Cov.: 6 AF XY: 0.0000550 AC XY: 14 AN XY: 254396

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000562

Gnomad4 OTH exome AF: 0.000112

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74282

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.26
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35739333; hg19: chr17-38083362;